tbuckley/cabot-search huggingface dataset:
P16.04.B Palliative CSF diversion in symptomatic leptomeningeal metastasis: a feasibility analysis of risks and benefits
Authors: O T Alhalabi, A W Unterberg, A Younsi
Journal: Neuro-Oncology (2022)

Abstract Background Leptomeningeal metastasis (LM) represents a terminal condition in a subset of patients with primary extra-cranial malignancies. With improved survival rates under novel systemic therapies for extra-cranial primary tumors, the role of cerebrospinal fluid (CSF) diversion via ventriculo-peritoneal shunts (VP-shunt) for symptom control of hydrocephalic LM is becoming increasingly important. This study hence aimed to describe this patient cohort and weigh out benefits against adverse events of palliative VP-shunt placement. Material and Methods A single-center retrospective analysis of all consecutive adult patients with VP-shunt placement over a period of six years was performed and clinical data (primary disease, clinical presentation, CSF diagnostics, previous therapies) in addition to surgical data (shunt devices, surgeries, and complications) and survival data were collected. Results were compared to a ‘non-oncological’ shunt cohort and statistical analyses was performed. Results 38 patients with a median age of 53 (18-78) years (13 males, 25 females) underwent VP-Shunt placement. The most common underlying oncological conditions were breast cancer (n=21, 55%) and non-small cell lung cancer (NSCLC, n=11, 29%). The median time between primary tumor and LM diagnosis was 23 months (0 to 180 months). 14 patients (37%) presented with end-stage disease at primary tumor diagnosis, 25 (66%) patients had cranial metastases. Most patients presented with classical symptoms of intracranial hypertension and 11 patients (38%) had already received intrathecal treatment or radiotherapy before shunting. After shunting, symptom relief was achieved in 30 patients (79%) and 24 patients (63%) were eventually discharged home after surgery. Subsequently, 63% of the shunted patients underwent systemic or radiotherapy and 55% received intrathecal therapy. Revision surgery was performed for valve malfunctions and infections (n=3, 8% for either) or distal catheter malposition (n=2, 5%) but comparison with a ‘non-oncological’ shunt cohort showed no differences in complication rates. Median survival from shunting was 2.1 months (95% CI 0.5 to 3 months). Conclusion VP-shunt placement could relieve symptoms of intracranial hypertension secondary to LM of primary solid tumors without a higher risk of shunt complications compared to non-oncological patients, with many LM patients persuing further oncologic therapy. However, decision-making regarding VP-shunt placement in LM patients still retains a palliative nature.
P08.13.A CaPaBLE - Assessing the Patient Generated Index Methodology in High Grade Glioma Patients and Caregivers
Authors: L Pakzad-Shahabi, J Tallant, K Le Calvez, M Wells, M Williams
Journal: Neuro-Oncology (2022)

Abstract Background CaPaBLE tests the feasibility and acceptability of assessing quality of life (QoL) using the patient-, or caregiver-generated index (PGI/CaGI) methodology in patients with HGG and their caregivers. Material and Methods CaPaBLE, (https://www.isrctn.com/ISRCTN45555598), followed patients and/ or their caregivers up to 6 months. Standard measures for patients were EORTC QLQ-C30/BN20, for caregivers the CarGOQOL questionnaire. The QoL topics raised through PGI/CaGI have been coded to the most relevant domain from their respective standard measure for an initial assessment of concordance. Results 36 patients, 24 caregivers recruited to study; completing an average of 3 study assessment timepoints. PGI and CaGI generated 240 and 160 topics respectively. Patient concerns most frequently coded to EORTC domain of Role Functioning; Caregiver concerns mostly coded to CarGOQOL domain of Burden. Other topics frequently raised by patients such as the driving and sex life, and future planning by caregivers are not specifically raised in standard questionnaires. Conclusion Nearly all topics raised by patients and caregivers were mapped to the domains of their respective standard QoL measure. However, almost half of all topics raised by patients and caregivers mapped to a minority of the domains included in standard measures; whilst a notable number of topics are not specifically included in standard measures at all. This raises questions regarding the efficiency and relevance of such questionnaires to patient and caregivers’ daily lives.
JS08.7.A Integrative analysis of longitudinal genomic and non-genetic mechanisms of radiotherapy-resistance in glioma
Authors: E Kocakavuk, F S Varn, K C Johnson, R G W Verhaak
Journal: Neuro-Oncology (2022)

Abstract Background Radiotherapy (RT) is a mainstay in the treatment of glioma patients, but RT-resistance is common. We have recently identified RT-associated genomic small deletion signatures, marking tumors that have developed resistance. Here, we used longitudinal molecular profiles to explore non-genetic mechanisms of RT-resistance. Material and Methods We have analyzed the multi-omic Glioma Longitudinal Analysis (GLASS) dataset, integrating DNA and RNA sequencing datasets from primary and post-treatment gliomas. Results We classified tumors as harboring temozolomide-associated hypermutation based on mutational burden increase (HM), and RT-associated signature based on small deletion burden increase (RTscars). By deconvoluting RNA profiles into cell state fractions, we observed an increase of a proliferating stem-like (PSL) cell state in 50% of patients with a RTscars+ signature which was significantly higher than RTscars-/HM- patients (P=8e-04, Fisher’s exact). PSL cell state increase associated with worse overall survival outcomes (P=1.5e-03, log-rank). We observed a significant correlation between the expression change of E2F cell cycle regulator genes (R=0.91, P=6.7e-04, Pearson) and EZH2 (R=0.81, P=8.3e-03) with the increase in the PSL cell state, nominating the E2F/EZH2-pathway as regulator of the PSL cell state. Furthermore, the RTscars signature was associated with an increase in frameshift neoantigens and significantly higher neoantigen burden at recurrence (P=2.4e-02, Kruskal-Wallis). This was accompanied by a significantly higher post-treatment T-cell fraction in RTscars+ tumors (P=8.2e-04, Wilcox), suggesting an increased T-cell infiltration in these patients. Conclusion Our analyses revealed a longitudinal increase in the proliferating stem-like cell state associated with RT-resistance and nominates the cell cycle pathway as an actionable target. The RT-associated deletion signature (RTscars) correlated with increased frameshift-neoantigens and T-cell fractions at recurrence, suggesting a potential benefit of a combinatorial immune-targeted therapy in this specific patient population.
P17.14.B Strategy of the recurrent Glioblastoma treatment. Three neuro-oncology centers study
Authors: O Kalita, T Kazda, S Reguli, R Jancalek, P Fadrus, L Krska, M Slachta, J Valosek, J Vrbkova, L Hrabalek, M Smrcka, R Lipina
Journal: Neuro-Oncology (2022)

Abstract Background The prognosis for patients with Glioblastoma (GBM) remains dismal. The most aggressive multimodal therapy (maximally radical and safe tumor resection, followed by the Stupp protocol oncotherapy) has yielded the best treatment outcomes. Notwithstanding the slowly prolonged patient′s overall survival, this tumor inevitable recurs. An optimal therapy of the recurrent GBM is still a controversial theme.The aim of our study is to evaluate our treatment strategy of recurrent GBM. Material and Methods For this study, we retrospectively selected a group of resected recurrent GBM patients in a period from June 1, 2009 to December 31, 2019, which were treated in tree Czech neuro-oncologic centers. All patients underwent early post-surgical MRI (within 72 h) to determine resection radicality. Following resection, patients received periodic checkups with MRI every 3 months until death. Patients with psedoprogession were excluded. Information about all surgeries, oncotherapies, patient clinical condition, MRI, PET/CT, and results of histological, immunohistochemical, molecular genetic, and cytogenetic investigations was gathered.We consider surgery for recurrent GBM in case, if: 1.The tumor volume increasing &amp;gt; 20-30% or tumor rediscovery after radiologic disappearing. 2.Clinic condition - Karnofsky score (KS) ≥ 70% and Performance status (PS) WHO ≤ gr. 2. 3.Localized tumor, without multilfocality. 4.Assumed the least tumor volume reduction &amp;gt; 80%. Results We gathered 122 patients with recurrent GBM, 98,9% of tumors was determined as wild-type, age median was 53,36 years. All patients underwent Stupp protocol oncotherapy after prime surgery. Median of OS from prime surgery was 21 months (15.8, 29.6). The best results proved a surgery of GBM recurrency proceeding more than 6 months after diagnosis. OS2 (from redo up to the death) was 7.4 months (6.41, 11.3). 43.3% of patients recalled temozolomide chemotherapy. We confirmed positive link between OS and resection radicality, negative relations between OS and a postoperative neurologic deficits. Only limited relation was presented between OS and repeated oncotherapy. Relation to the further histologic, imunohistochemic, cytogenetic and molecular markers will be discussed. Conclusion Due to the common unfavorable outcomes of GBM therapy, out of despair, we often decided for repeated surgery. The aim of our study was avoid ineffective surgical overtreatment. The best results of surgery yield right selected recurrent GBMs. Surgery of GBM regrown during initial oncotherapy (6 months after prime surgery) presented unsatisfactory effects. Positive effect of the surgical radicality and clinic status were confirmed. Again, necessity of second-line oncotherapy has been emerged. Supported by Ministry of Health of the Czech Republic, grant nr. NV19- 04-00281 and grant nr. NU21-03-00195
P11.09.B Chemotherapy is an efficient treatment in primary CNS MALT lymphoma
Authors: C Desjardins, D Larrieu-Ciron, S Choquet, K Mokhtari, F Charlotte, L Nichelli, B Mathon, G Ahle, M Le Garff-Tavernier, C Dehais, K Hoang-Xuan, C Houillier
Journal: Neuro-Oncology (2022)

Abstract Background Mucosae-associated lymphoid tissue (MALT) lymphomas are a rare and still poorly understood form of primary central nervous system lymphoma (PCNSL). The aim of this study was to better describe these tumors and their management, and to better appreciate their long-term prognosis after treatment. Material and Methods Adult immunocompetent patients with primary CNS MALT lymphoma (PCNSML) were retrospectively selected from the database on PCNSL of the Pitié-Salpêtrière Hospital. All cases had double-read for pathology. Results Eleven PCNSML representing 1.7% of the 662 PCNSL included in the database were selected, There were 9 women and two men, all immunocompetent. Their median age was 56 years (min 29; max 78). The median time from first symptoms to diagnosis was 13 months and the median KPS at diagnosis was 90. Location was dural in 8 cases, suggestive of meningioma in 7 cases and of subdural hematoma in 1 case, and parenchymal in 3 cases. The disease was unifocal/localized in 4 cases and multifocal/diffuse in 7 cases. In 3 cases, it was the second reading that allowed making the diagnosis. In first-line treatment, all patients received chemotherapy (CT): “systemic” CT, i.e usually used in systemic MALT lymphomas, in 7 cases (n=7) and “CNS” CT, i.e usually used in CNS lesions in 4 cases. CT was preceded by surgery in 4 cases. No patient received radiotherapy in first line. According to the IPCG (International PCNSL Collaborative Group) criteria, the overall response rate was 7/11 (64%). At latest news, 5 patients had a persistent contrast enhancement, stable without any treatment since a median of 57 months, raising the question of complete response despite persisting contrast enhancement. No patient developed neurotoxicity except for one of the 2 patients who subsequently received radiotherapy. The median follow-up was 109 months. The median progression-free survival was 78.0 months (95% CI [43.4;NA[) and the 10-year overall survival rate was 90% (95% CI [0.7;1[). Conclusion This series confirms the classical clinical and radiological presentation of PCNSML. Compared to the literature where the treatment was based on radiotherapy in almost two thirds of cases, the therapeutic approach presented here appears unconventional. This is the first series demonstrating that chemotherapy is an efficient treatment in PCNSML, with an excellent long-term outcome and the absence of neurotoxicity, and calling into question the relevance of the IPCG criteria for the evaluation of their therapeutic response.
P11.43.B The impact of neutrophils-to-lymphocytes ratio on survival in patients affected by brain metastases and treated with Gamma Knife Radiosurgery
Authors: F Gagliardi, S Snider, F Roncelli, E Pompeo, P De Domenico, V Klungtvedt, L Barzaghi, A Bulotta, C Lazzari, A Del Vecchio, P Mortini
Journal: Neuro-Oncology (2022)

Abstract Background The Neutrophil-to-Lymphocyte ratio (NLR) is a biomarker for host systemic inflammation. Elevated NLR may result from neutrophilia, lymphopenia or both and is associated with poor prognosis and treatment responses in various malignant tumors, such as breast, gastric, colorectal and lung cancer. It was found that in patients treated with GK-SRS for brain metastases (BM) from non-small cell lung cancer (NSCLC), median survival was significantly longer in patients with NLR &amp;lt; 5 at the time of radiosurgery and after treatment (within 1 month from SRS). High percentage of neutrophils, low percentage of lymphocytes and elevated platelet-to-lymphocyte ratio were predictive of poor OS in patients with brain metastases. Further evidences are needed to support and better define these findings. Material and Methods We retrospectively examined 111 consecutive patients with BMs from NSCLC (95 patients) and melanoma (16 patients) treated with GK-SRS. A total of 695 lesions were treated (median lesion number per patient 6; range 1-18), the median volume was 0.108 cc (range 0.004-33.44 cc). NLR was calculated using N/L, where N and L, respectively, refer to peripheral blood neutrophils (N) and lymphocyte (L) counts at the timepoint nearest to the SRS treatment. Kaplan-Meier analysis described the survival time according to NLR. Univariable and multivariable Cox regression analyses were used to confirm the impact of NLR on overall survival. Results Median (IQR) age at diagnosis of brain metastases was 64 yrs (55-70), median (IQR) NLR was 6.7 (1.3-32), and median (IQR) overall survival was 13.5 months (1-42). At univariable Cox-regression analyses, lower NLR was associated with improved overall survival (HR: 1.05; p=0.004). Total number of lymphocytes, neutrophils and monocytes were not associated with improved overall survival (all p&amp;gt;0.1). At multivariable Cox regression analyses, after adjusting for patient age, sex and the use of DEX therapy, NLR represented an independent predictor of overall survival (HR: 1.06; p=0.003). Conclusion NLR represents an independent prognostic factor in patients affected by BMs from NSCLC and melanoma. Inflammation and immunity may play a critical role in these patients. Further analysis examining more specific neutrophils or lymphocytes subsets may increase our understanding of cancer etiology and progression.
P10.13.B Repurposing neuroleptics to treat brain metastases: Clozapine as a novel therapy for melanoma brain metastases
Authors: T Wikerholmen, E Taule, F A Thorsen, T Sundstrøm
Journal: Neuro-Oncology (2022)

Abstract Background Around half of advanced melanoma patients develop brain metastases (BM) and survival is still measured in months. Current treatments, although increasingly effective, are not sufficient for this patient group, necessitating development of new therapeutic options. Drugs targeting BM specifically are a scarcity. However, utilizing drug repurposing, i.e. novel uses of drugs already approved for other medical conditions, may broaden available therapy options. Medications used to treat psychosis can penetrate an intact blood-brain barrier and it has been shown that patients with schizophrenia have lower incidences of certain cancer types than the rest of the population. Still, little is known on antitumor effects of neuroleptics on BM. We have preliminary data showing that the antipsychotic drug clozapine effectively inhibits growth of human melanoma brain metastasis (MBM) cell lines in vitro. Material and Methods We used the H1, H2, H3 and H10 MBM cell lines, as well as normal human astrocytes (NHA). Monolayer viability and IncuCyte studies were performed to determine IC50 doses. Cell migration was measured by a scratch wound assay. Apoptosis was studied by flow cytometry. Colony formation assays were performed using 2D clonogenic assays and 3D soft agar models. A protein array was used to find signaling proteins potentially affected by clozapine. The effect of clozapine on the normal brain was assessed, using a novel brain organoid model developed from fetal rat brains. Results A viability screening using 6 different neuroleptics showed that clozapine was most effective in inhibiting MBM cell viability, while NHA tolerated the same doses. MBM cells exhibited a dose-dependent inhibition of cell proliferation, migration, clonogenic formation and 3D growth. Flow cytometry demonstrated that apoptosis was a major mechanism of cytotoxicity. The protein array showed that CCL3, IL8 and VEGF were downstream targets of clozapine. These results are currently being confirmed by western blots. Doses significantly above MBM IC50 doses did not affect viability of brain organoids. Currently, a partnership with the Dept. of Chemistry (UiB) has been initiated to develop and test novel clozapine derivates, to find a more effective derivative with a larger therapeutic window and lesser side effects. Conclusion Clozapine shows promise as a novel agent for use in cancer therapy due its favorable tolerability, small molecular size and established clinical safety.
P11.51.B Initial temozolomide monotherapy without radiotherapy might be of limited benefit in the treatment of astrocytoma, IDH-mutant, CNS WHO grade 2 and 3
Authors: J Weller, S Katzendobler, J Blobner, S Quach, R Egensperger, B Suchorska, N Thon, M Weller, J Tonn
Journal: Neuro-Oncology (2022)

Abstract Background The role of temozolomide chemotherapy alone in isocitrate dehydrogenase (IDH-) mutant astrocytomas has not been conclusively determined. Radiotherapy might be superior to temozolomide alone. Recent studies have linked temozolomide therapy with poor clinical course and induction of hypermutation in IDH-mutant gliomas. Material and Methods In this retrospective, single-center study, 183 patients with astrocytoma, IDH-mutant, CNS WHO grade 2 or 3 according to WHO 2021 and diagnosed between 2000 and 2019 were included. Patients initially monitored by means of a wait-and-scan strategy, or treated with radiotherapy alone, or receiving temozolomide alone after histological sampling through biopsy or tumor resection were studied. Patient-related, clinical and imaging data were correlated with progression-free and overall survival. A matched-pair analysis accounting for post-surgical tumor volume was conducted. Results No significant differences in median age and clinical status at diagnosis was seen. WHO grades were balanced between patients treated with radiotherapy and temozolomide, but the proportion of WHO grade 2 gliomas was higher in the wait-and-scan cohort. Radiotherapy was associated with significantly longer overall survival than temozolomide (in years, 14.4 vs 10.7; p=0.02) and longer progression-free survival than temozolomide (in years, 6.2 vs 3.4, p=0.02) and wait-and-scan strategies (in years, 6.2 vs 4; p=0.03). Comparing wait-and-scan with temozolomide, survival was significantly longer in the wait-and-scan cohort (in years, not reached vs 10.7, p&amp;lt;0.0001). An analysis of WHO grade 2 astrocytomas only also showed superior survival in the wait-and-scan cohort as compared to temozolomide (p=0.02). Of note PFS was similar overall and in WHO grade 2 astrocytomas. Conclusion The results suggest superiority of radiotherapy alone over temozolomide alone or wait-and-scan strategies in IDH-mutant WHO grade 2 and 3. Recent study results indicating that temozolomide might compromise prognosis in some IDH-mutant gliomas might be supported by our data, although caution in interpretation of retrospective data is required. The potential negative effects may only be apparent in the long-term.
P15.01.A Metabolic-imaging of human glioblastoma explants: a new precision-medicine model to predict treatment response early
Authors: M Morelli, F Lessi, A Di Stefano, O Santonocito, C Gambacciani, F Pieri, F Aquila, G Ferri, M Snuderl, P Mulholland, D Ottaviani, P Aretini, F Pasqualetti, S Franceschi, C Mazzanti
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma (GB) is the most severe form of brain cancer, with a 12-15 month median survival. Although cell therapies for GB are on the near horizon, surgical resection, temozolomide (TMZ) and radiotherapy (RT) remain the primary therapeutic options for GB, and no new small-molecule therapies have been introduced in recent years. This therapeutic standstill is partially because preclinical models of GB do not reflect the complexities of GB cell biology. Furthermore, the aggressive progression of GB makes it critical to identify patient-tailored therapeutic strategies early. Material and Methods We developed a novel in-vitro 3D glioblastoma explants (GB-EXPs) model derived from patients’ resected tumors maintaining cytoarchitecture seen in the tumors. We then performed metabolic-imaging by fluorescence lifetime imaging microscopy (FLIM) on live GB-EXPs to predict drug response, using TMZ as test drug. Results The entire process was successfully completed within 1 week since surgery. A unique drug response sample stratification emerged that was well reflected at the molecular level, highlighting new targets associated with TMZ treatment and identifying a molecular signature associated with survival. Conclusion To the best of our knowledge, this is the first time that FLIM-based metabolic imaging is used on live glioblastoma explants to test anti-neoplastic drugs. FLIM-based readouts of drug response in GB explants could accelerate precision treatment of patients with GB and the identification of new anti-GB drugs.